文章：

NF-κB激活的癌基因抑制策略用于癌症基因治疗

NF-κB-activated oncogene inhibition strategy for cancer gene therapy 

原文发布日期：2024-09-03 

英文摘要：

NF-κB is a promising target for cancer treatment because of its overactivation in almost all cancers but countless NF-κB inhibitors rarely became clinical drugs due to side effects. In contrast to traditional cancer treatments aimed at inhibiting NF-κB activity, this study develop a novel approach termed HOPE, which focuses on activating the exogenous effector gene CRISPR-Cas13a within cancer cells, achieved by utilizing the NF-κB-specific promoter DMP previously constructed, then targets and suppresses the expression of oncogenes TERT, PLK1, KRAS and MYC at mRNA level. We evaluated the antitumour effects of HOPE in various cultured cells and confirmed it could induce obvious the death of cancer cells without affecting normal cells. By packaging HOPE into adeno-associated virus (AAV) and intravenously injected it to treat mice that were subcutaneously transplanted with colorectal cancer. This validated that rAAV-HOPE could significantly inhibit tumour growth without side effects. Based on the scRNA-seq data, we observed that HOPE could activate the immune system and decrease the proportion of cancer cells, particularly reducing the stemness of cancer cells. This study elucidates an important role of HOPE in inhibiting cancer cell growth both in vitro and in vivo, additionally provides a novel therapeutic technology for cancer gene therapy. 

摘要翻译：

NF-κB因其在几乎所有癌症中的过度激活而成为癌症治疗的重要靶点，但无数NF-κB抑制剂因副作用问题罕有成为临床药物。与传统旨在抑制NF-κB活性的癌症治疗策略不同，本研究开发了一种名为HOPE的新方法：通过利用先前构建的NF-κB特异性启动子DMP，在癌细胞内激活外源效应基因CRISPR-Cas13a的表达，进而靶向抑制端粒酶逆转录酶（TERT）、 Polo样激酶1（PLK1）、KRAS和MYC等癌基因在mRNA水平的表达。我们在多种培养细胞中评估了HOPE的抗肿瘤效果，证实其能显著诱导癌细胞死亡而不影响正常细胞。通过将HOPE包装至腺相关病毒（AAV）中，并对皮下移植结直肠癌的小鼠进行静脉注射治疗，验证了rAAV-HOPE能显著抑制肿瘤生长且无副作用。基于单细胞RNA测序数据，我们观察到HOPE可激活免疫系统并降低癌细胞比例，尤其能显著降低癌细胞的干性特征。本研究阐明了HOPE在体外和体内抑制癌细胞生长的重要作用，并为癌症基因治疗提供了新型治疗技术。

原文链接：

NF-κB-activated oncogene inhibition strategy for cancer gene therapy